Solid forms of stemospironine and its salts

Abstract

Disclosed are stemospironine salts of Formula 1: wherein HX represents HCl, HBr, L-tartaric acid, D-tartaric acid, sulfuric acid, (+)-(1S)-10-camphorsulfonic acid, ethanesulfonic acid and ethane-1,2-disulfonic acid. This invention also provides crystalline polymorph forms of the compound of Formula 1 wherein HX is HCl, stemospironine hydrochloride. This invention also provides a new crystalline form of the compound of Formula 2, stemospironine free base: Also disclosed are compositions containing one or more compounds of Formula 1, methods for controlling cough comprising administering a therapeutically effective amount of a compound of Formula 1, and methods for preparing compounds of Formula 1. Also disclosed is a method for preparing crystalline stemospironine hydrochloride polymorph Form II from stemospironine hydrochloride polymorph Form I. ##STR00001##

Claims

1. A crystalline stemospironine salt of Formula 1, ##STR00004## wherein HX is hydrogen chloride, in the form of a polymorph Form I that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00011 2θ 8.818 9.333 13.806 14.065 14.853 15.568 15.931 17.514 18.621 18.966 20.494 22.731 24.228 25.159 26.217 27.697 28.455 29.167 30.124 32.384 33.101 33.584.

2. A crystalline stemospironine salt of Formula 1, ##STR00005## wherein HX is hydrogen chloride, in the form of a polymorph Form II that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00012 2θ 8.772 9.294 13.795 14.137 14.825 15.47 15.889 17.456 18.579 22.702 23.047 24.39 25.128 25.593 26.174 27.929 28.389 29.153 29.993 32.39 33.083 33.55 36.186 37.594 39.215 39.851 42.139.

3. A crystalline stemospironine salt of Formula 1, ##STR00006## wherein HX is hydrogen bromide, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00013 2θ 8.664 9.434 13.648 14.179 15.188 15.84 17.588 20.174 21.559 22.755 23.644 24.567 25.924 26.445 27.666 27.949 28.827 29.306 30.268 31.1 32.198 33.95 36.298 42.236.

4. A crystalline stemospironine salt of Formula 1, ##STR00007## wherein HX is L-tartaric acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00014 2θ 10.873 12.296 14.346 15.269 16.703 17.363 18.277 18.979 19.871 20.409 22.259 23.388 24.589 25.362 26.002 26.96 27.551 28.973 29.758 30.31 31.063 31.914 35.009 35.603 36.677 37.476 38.172 38.918 39.497 40.682 41.781.

5. A crystalline stemospironine salt of Formula 1, ##STR00008## wherein HX is D-tartaric acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00015 2θ 9.834 11.641 12.342 13.487 14.967 15.957 17.457 18.57 19.583 20.583 21.63 22.655 24.738 25.312 27.084 27.63 29.432 30.163 31.035 34.582 35.16 36.489 38.156 40.849 41.401.

6. A crystalline stemospironine salt of Formula 1, ##STR00009## wherein HX is sulfuric acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00016 2θ 7.13 9.257 9.801 14.061 15.365 16.515 18.379 19.319 20.778 22.888 23.794 25.016 25.931.

7. A crystalline stemospironine salt of Formula 1, ##STR00010## wherein HX is (+)-(1S)-10-camphorsulfonic acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00017 2θ 6.519 9.225 12.798 13.237 13.696 14.586 15.136 17.005 17.474 18.221 19.393 20.411 21.673 22.6 23.431 24.022 26.059 27.062 29.172 32.865 38.199.

8. A crystalline stemospironine salt of Formula 1, ##STR00011## wherein HX is ethanesulfonic acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00018 2θ 7.32 7.847 9.597 12.406 13.611 15.135 15.816 17.558 17.928 18.596 19.139 19.99 21.484 22.063 22.721 23.671 25.139 26.022 27.916 28.39 29.297 29.894 31.844 34.902 35.639 36.154 36.701 37.276.

9. A crystalline stemospironine salt of Formula 1, ##STR00012## wherein HX is 1,2-ethanedisulfonic acid, that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00019 2θ 9.067 10.94 11.385 12.92 13.546 14.129 15.391 17.292 17.842 19.703 20.246 20.8 21.158 21.827 22.768 23.55 24.438 25.361 26.736 27.319 27.642 28.393 29.485 30.552 30.959 33.172 35.006 35.509 36.309 37.155 37.722 38.359 41.195.

10. A crystalline form of the compound of Formula 2, stemospironine free base, ##STR00013## that exhibits an X-ray powder diffraction pattern having at least the following 2θ reflection positions: TABLE-US-00020 2θ 9.959 10.304 12.927 13.318 14.535 15.216 17.515 17.952 19.701 21.435 22.634 23.978 24.575 25.53 26.285 28.543 31.009.

11. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising one or more compounds of claim 2 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising one or more compounds of claim 3 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising one or more compounds of claim 4 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising one or more compounds of claim 5 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising one or more compounds of claim 6 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising one or more compounds of claim 7 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising one or more compounds of claim 8 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising one or more compounds of claim 9 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising one or more compounds of claim 10 and a pharmaceutically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows a characteristic X-ray powder diffraction pattern of crystalline polymorph Form I of the 1:1 hydrochloric acid salt of stemospironine.

(2) FIG. 2 shows a characteristic X-ray powder diffraction pattern of crystalline polymorph Form II of the 1:1 hydrochloric acid salt of stemospironine.

(3) FIG. 3 shows a characteristic pattern of crystalline 1:1 hydrobromic acid salt of stemospironine.

(4) FIG. 4 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 L-tartaric acid salt of stemospironine.

(5) FIG. 5 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 D-tartaric acid salt of stemospironine.

(6) FIG. 6 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 sulfuric acid salt of stemospironine.

(7) FIG. 7 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 (+)-(1S)-10-camphorsulfonic acid salt of stemospironine.

(8) FIG. 8 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 ethanesulfonic acid salt of stemospironine.

(9) FIG. 9 shows a characteristic X-ray powder diffraction pattern of crystalline 1:1 1,2-ethanedisulfonic acid salt of stemospironine.

(10) FIG. 10 shows a characteristic X-ray powder diffraction pattern of crystalline stemospironine.

DETAILED DESCRIPTION OF THE INVENTION

(11) As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers and/or dosage forms which are suitable for use in contact with the tissues of human beings and excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

(12) As used herein, the term “effective amount of” refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination as an antitussive agent.

(13) The term crystalline “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved solubility, etc.), relative to another polymorph or a mixture of polymorphs of the same compound. Preparation and isolation of a particular polymorph of a compound can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.

(14) Embodiments of the present invention as described in the Summary of the Invention include:

(15) Embodiment 1. The salt of Formula I described in the Summary of the Invention in crystalline form.

(16) Embodiment 2. The salt of Embodiment 1 wherein HX is hydrogen chloride, in the form of a polymorph Form I that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 1.

(17) Embodiment 3. The salt of Embodiment 1 wherein HX is hydrogen chloride, in the form of a polymorph Form I that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 1.

(18) Embodiment 4. The salt of Embodiment 1 wherein HX is hydrogen chloride, in the form of a polymorph Form II that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 2.

(19) Embodiment 5. The salt of Embodiment 1 wherein HX is hydrogen chloride, in the form of a polymorph Form II that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 2.

(20) Embodiment 6. The salt of Embodiment 1 wherein HX is hydrogen bromide, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 3.

(21) Embodiment 7. The salt of Embodiment 1 wherein HX is hydrogen bromide, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 3.

(22) Embodiment 8. The salt of Embodiment 1 wherein HX is L-tartaric acid, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 4.

(23) Embodiment 9. The salt of Embodiment 1 wherein HX is L-tartaric acid, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 4.

(24) Embodiment 10. The salt of Embodiment 1 wherein HX is D-tartaric acid that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 5.

(25) Embodiment 11. The salt of Embodiment 1 wherein HX is D-tartaric acid that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 5.

(26) Embodiment 12. The salt of Embodiment 1 wherein HX is sulfuric acid, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 6.

(27) Embodiment 13. The salt of Embodiment 1 wherein HX is sulfuric acid, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 6.

(28) Embodiment 14. The salt of Embodiment 1 wherein HX is (+)-(1S)-10-camphorsulfonic acid, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 7.

(29) Embodiment 15. The salt of Embodiment 1 wherein HX is (+)-(1S)-10-camphorsulfonic acid, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 7.

(30) Embodiment 16. The salt of Embodiment 1 wherein HX is ethanesulfonic acid, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 8.

(31) Embodiment 17. The salt of Embodiment 1 wherein HX is ethanesulfonic acid, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 8.

(32) Embodiment 18. The salt of Embodiment 1 wherein HX is 1,2-ethanedisulfonic acid, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 9.

(33) Embodiment 17. The salt of Embodiment 1 wherein HX is 1,2-ethanedisulfonic acid, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 9.

(34) Embodiment 18. A crystalline form of the compound of Formula 2, i.e. stemospironine free base, that exhibits an X-ray powder diffraction pattern as exemplified in FIG. 10.

(35) Embodiment 19. A crystalline form of the compound of Formula 2, i.e. stemospironine free base, that exhibits an X-ray powder diffraction pattern having characteristic peaks, expressed in degrees 2θ, as shown in Table 10.

(36) This invention provides a pharmaceutical composition comprising one or more compounds of Formula 1 and a pharmaceutically acceptable carrier. Of note as embodiments of such compositions are compositions comprising a compound corresponding to any of the embodiments described above.

(37) This invention provides a method of controlling cough comprising administering to a human a therapeutically effective amount of a compound of Formula 1. Of note as embodiments of such methods are methods comprising applying a therapeutically effective amount of a compound corresponding to any of the embodiments described above. Of particular note are embodiments where compounds are applied as compositions of this invention. Also of particular note are embodiments where compounds are administered orally.

(38) The present invention further discloses a method for preparing crystalline stemosporinine salts of Formula 1 from stemosporinine, a compound of Formula 2, and an acid HX, comprising: A) dissolving the compound of Formula 2, stemospironne, in a suitable first solvent to form a solution A; B) adding an acid HX, optionally dissolved in a sutiable second solvent, to solution A to form a reaction mixture; C) optionally adding a third solvent; and D) separating the resulting solid, i.e. a compound of Formula 1, from the reaction mixture.

(39) The first and second solvents are independently selected from the group consisting of water, methanol, ethanol, isopropanol and acetonitrile.

(40) The third solvent is independently selected from the group consisting of methyl tert-butyl ether, heptane and hexane.

(41) The acid HX is selected from the group consisting of hydrogen chloride, hydrogen bromide, L-tartaric acid, D-tartaric acid, sulfuric acid, (+)-(1S)-10-camphorsulfonic acid, ethanesulfonic acid and ethane-1,2-disulfonic acid.

(42) The present invention further discloses a method for preparing crystalline stemospironne hydrochloride polymorph Form II comprising: A) dissolving crystalline stemospironne hydrochloride polymorph Form I in acetonitrile at 50° C.; B) evaporating said acetonitrile solution at at 50° C.; C) recovering crystalline stemospironne hydrochloride polymorph Form II; and D) drying said stemospironne hydrochloride polymorph Form II.

(43) The polymorph salts of the present invention (i.e. a compound of Formula 1 wherein HX is hydrogen chloride) may be in a non-solvated form or a solvated form, in particular in a hydrated form or an alcoholated form.

(44) The polymorph salts of the present invention (i.e. a compound of Formula 1 wherein HX is hydrogen chloride) may be in an amorphous form or in various crystalline forms thereof, or in a form of a mixture of these forms.

(45) Polymorph forms of the present invention are characterized by the peaks appearing in the X-ray powder diffraction (XRPD) pattern. The XRPD patterns of the polymorphs of this invention were measured by a Rigaku Miniflex X-ray Powder Diffractometer (XRPD) instrument.

(46) X-ray radiation is from Copper Cu at 1.054056 Å with K.sub.β filter. X-ray power is 30 KV, 15 mA. Sample powder is dispersed on a zero-background sample holder. General measurement conditions are: start angle −3; stop angle −45; scan speed −2 deg/min.

Example 1a

(47) Preparation of Polymorph Form I of the 1:1 Hydrochloric Acid Salt of Stemospironine

(48) A stirred suspension of stemospironine (2.24 g, 6.37 mmol) in methanol (15 mL) was heated to 55° C. over 15 min. To the resulting solution was added 1.0 M hydrogen chloride in isopropanol (7.33 mL, 7.33 mmol, 1.15 equiv) followed by methyl tert-butyl ether, and the resulting slurry was stirred at room temperature for 8 h. The resulting solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried under reduced pressure at 20-21° C. to afford the title compound (1.32 g, 92.6%) as a crystalline solid which was characterized by XRPD. FIG. 1 shows a characteristic X-ray powder diffraction (XRPD) pattern of polymorph Form 1 of the 1:1 hydrochloric acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 1.

(49) TABLE-US-00001 TABLE 1 Angle 2θ [°] Relative Intensity (%) 8.818 42.1 9.333 43.2 13.806 9.3 14.065 9 14.853 40.6 15.568 100 15.931 38.9 17.514 42.7 18.621 9.6 18.966 4.8 20.494 10 22.731 41.2 24.228 48.7 25.159 85.2 26.217 35.3 27.697 33.9 28.455 44.2 29.167 23.9 30.124 13.4 32.384 25.4 33.101 33.8 33.584 9.3

Example 1b

(50) Preparation of Polymorph Form II of the 1:1 Hydrochloric Acid Salt of Stemospironine

(51) Evaporation of an acetonitrile solution of the polymorph Form I of the 1:1 hydrochloric acid salt of stemospironine (prepared as described in Example 1a) at 50° C. afforded the title compound which was characterized by XRPD. FIG. 2 shows a characteristic X-ray powder diffraction (XRPD) pattern of polymorph Form II of the 1:1 hydrochloric acid salt of stemosporinine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 2.

(52) TABLE-US-00002 TABLE 2 Angle 2θ [°] Relative Intensity (%) 8.772 8.4 9.294 100 13.795 26.7 14.137 8.3 14.825 6.6 15.47 25.6 15.889 14.7 17.456 13.3 18.579 23.2 22.702 20.8 23.047 9.5 24.39 39.2 25.128 18.1 25.593 8.5 26.174 24.6 27.929 22.4 28.389 6.9 29.153 11.3 29.993 28 32.39 11.9 33.083 7.4 33.55 8.1 36.186 4.2 37.594 11 39.215 5.3 39.851 7.8 42.139 4.7

Example 2

(53) Preparation of the 1:1 Hydrobromic Acid Salt of Stemospironine

(54) Using the method of Example 1a, the title compound (96.3%) was obtained as a crystalline solid which was characterized by XRPD. FIG. 3 shows a characteristic X-ray powder diffraction (XRPD) pattern of stemospironine monohydrobromide. Characteristic peaks, expressed in degrees 2θ, are listed in Table 3.

(55) TABLE-US-00003 TABLE 3 Angle 2θ [°] Relative Intensity (%) 8.664 10.9 9.434 67.3 13.648 4.7 14.179 13.8 15.188 7.1 15.84 45 17.588 19.4 20.174 12.4 21.559 5.6 22.755 54.7 23.644 17.8 24.567 100 25.924 42.1 26.445 8.8 27.666 22.4 27.949 33.5 28.827 9.2 29.306 20.1 30.268 14.1 31.1 5.1 32.198 29.4 33.95 13 36.298 14.6 42.236 7.3

Example 3

(56) Preparation of the 1:1 L-Tartaric Acid Salt of Stemospironine

(57) To a stirred solution of stemosporinnne (395 mg, 1.14 mmol) and L-tartaric acid (195 mg, 1.29 mmol, 1.15 equiv) in acetonitrile (3 mL) and methanol (1 mL) was added methyl tert-butyl ether (5 mL), and the resulting slurry was stirred at room temperature for 5 h. The resulting solid was filtered, washed with methyl tert-butyl ether (1.5 mL) and dried under reduced pressure at 20-21° C. to afford the title compound (553 mg, 98.0%) as a crystalline solid which was characterized by XRPD. FIG. 4 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 L-tartaric acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 4.

(58) TABLE-US-00004 TABLE 4 Angle 2θ [°] Relative Intensity (%) 10.873 59.5 12.296 42.4 14.346 5 15.269 100 16.703 28.5 17.363 53.7 18.277 62.5 18.979 40.6 19.871 10.6 20.409 42.3 22.259 29.8 23.388 47.9 24.589 18.2 25.362 42.2 26.002 21.6 26.96 15.9 27.551 5.5 28.973 21.3 29.758 8.1 30.31 6.3 31.063 11.2 31.914 15.4 35.009 22.4 35.603 12 36.677 8 37.476 8.3 38.172 9.2 38.918 6.8 39.497 5.1 40.682 4.5 41.781 6

Example 4

(59) Preparation of the 1:1 D-Tartaric Acid Salt of Stemospironine

(60) Using the method of Example 3 stemosporinnne and D-tartaric acid yielded the title compound as a crystalline solid which was characterized by XRPD. FIG. 5 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 D-tartaric acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 5.

(61) TABLE-US-00005 TABLE 5 Angle 2θ [°] Relative Intensity (%) 9.834 100 11.641 12.9 12.342 3.5 13.487 3.1 14.967 3.3 15.957 48.1 17.457 6.3 18.57 14.4 19.583 20.2 20.583 46.4 21.63 5 22.655 19.4 24.738 8.8 25.312 6.8 27.084 7.2 27.63 4 29.432 8.9 30.163 7 31.035 6.6 34.582 3.8 35.16 4.3 36.489 5.6 38.156 3.5 40.849 1.5 41.401 1.9

Example 5

(62) Preparation of the 1:1 Sulfuric Acid Salt of Stemospironine

(63) Using the method of Example 3 stemosporinnne and sulfuric acid yielded the title compound as a crystalline solid which was characterized by XRPD. FIG. 6 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 sulfuric acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 6.

(64) TABLE-US-00006 TABLE 6 Angle 2θ [°] Relative Intensity (%) 7.13 100 9.257 13.4 9.801 5.8 14.061 19.5 15.365 10 16.515 11 18.379 7.7 19.319 7.5 20.778 34 22.888 11.1 23.794 10.3 25.016 11.2 25.931 6.5

Example 6

(65) Preparation of the 1:1 (+)-(1S)-10-Camphorsulfonic Acid Salt of Stemospironine

(66) Using the method of Example 3 stemosporinnne and (+)-(1S)-10-camphorsulfonic acid, yielded the title compound as a crystalline solid which was characterized by)(RFD. FIG. 7 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 (+)-(1S)-10-camphorsulfonic acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 7.

(67) TABLE-US-00007 TABLE 7 Angle 2θ [°] Relative Intensity (%) 6.519 100 9.225 7.5 12.798 11.9 13.237 23.4 13.696 3.3 14.586 36.9 15.136 17.7 17.005 37.1 17.474 5.8 18.221 35 19.393 20.9 20.411 50.1 21.673 9.8 22.6 30.9 23.431 12.3 24.022 22.7 26.059 13.1 27.062 12.5 29.172 12.2 32.865 7.9 38.199 7

Example 7

(68) Preparation of the 1:1 Ethanesulfonic Acid Salt of Stemospironine

(69) Using the method of Example 3 stemosporinnne and ethanesulfonic acid yielded the title compound as a crystalline solid which was characterized by XRPD. FIG. 8 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 ethanesulfonic acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 8.

(70) TABLE-US-00008 TABLE 8 Angle 2θ [°] Relative Intensity (%) 7.32 100 7.847 1.1 9.597 11.1 12.406 3.3 13.611 5.3 15.135 10.4 15.816 8.7 17.558 2.8 17.928 6.5 18.596 15.5 19.139 5.9 19.99 3.2 21.484 4.6 22.063 3.7 22.721 68.3 23.671 10.7 25.139 18.4 26.022 4.9 27.916 3.7 28.39 3.9 29.297 16 29.894 8.1 31.844 4.9 34.902 3.9 35.639 7.3 36.154 5.1 36.701 7.2 37.276 2.4

Example 8

(71) Preparation of the 1:1 1,2-Ethanedisulfonic Acid Salt of Stemospironine

(72) Using the method of Example 3 stemosporinnne and 1,2-ethanedisulfonic acid yielded the title compound as a crystalline solid which was characterized by XRPD. FIG. 9 shows a characteristic X-ray powder diffraction (XRPD) pattern of the 1:1 1,2-ethanedisulfonic acid salt of stemospironine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 9.

(73) TABLE-US-00009 TABLE 9 Angle 2θ [°] Relative Intensity (%) 9.067 9.7 10.94 84.3 11.385 24.9 12.92 55 13.546 15.2 14.129 56.4 15.391 52.4 17.292 93.8 17.842 16.3 19.703 72.1 20.246 34.7 20.8 21.1 21.158 100 21.827 29.5 22.768 44.3 23.55 22.3 24.438 58.7 25.361 89.5 26.736 44.4 27.319 15.5 27.642 18.6 28.393 44.2 29.485 11.4 30.552 12.7 30.959 11.3 33.172 11.5 35.006 10.9 35.509 17.4 36.309 7 37.155 13.6 37.722 6.9 38.359 5.7 41.195 19

Example 9

(74) Preparation of Crystalline Stemospironine Free Base

(75) Evaporation of an acetonitrile solution of the stemospironine free base at 25° C. afforded the title compound which was characterized by XRPD. FIG. 10 shows a characteristic X-ray powder diffraction (XRPD) pattern of crystalline stemosporinine. Characteristic peaks, expressed in degrees 2θ, are listed in Table 10.

(76) TABLE-US-00010 TABLE 10 Angle 2θ [°] Relative Intensity (%) 9.959 10.9 10.304 2.3 12.927 18.2 13.318 6 14.535 6.6 15.216 5.3 17.515 4.5 17.952 4.6 19.701 100 21.435 10.5 22.634 3.7 23.978 2 24.575 1.9 25.53 4.3 26.285 8.3 28.543 4.9 31.009 5.7